The Effect of Anxiety and Depression on Improvements in Pain in a Randomized, Controlled Trial of Pregabalin for Treatment of Fibromyalgia

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1 Blackwell Publishing IncMalden, USAPMEPain Medicine American Academy of Pain Medicine? RESEARCH ARTICLEAnxiety and Depression in Fibromyalgia PatientsArnold et al. PAIN MEDICINE Volume 8 Number The Effect of Anxiety and Depression on Improvements in Pain in a Randomized, Controlled Trial of Pregabalin for Treatment of Fibromyalgia Lesley M. Arnold, MD,* Leslie J. Crofford, MD, Susan A. Martin, MSPH, James P. Young, MS, and Uma Sharma, PhD *Women s Health Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Rheumatology & Women s Health, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky; Pfizer Global Research and Development, Ann Arbor, Michigan, USA ABSTRACT ABSTRACT Objective. To assess symptoms of anxiety and depression in a large cohort of fibromyalgia patients and to determine the impact of these symptoms on response of pain to pregabalin treatment. Design. Patients completed the Hospital Anxiety and Depression Scale at the baseline visit in a randomized, controlled trial of pregabalin for treatment of fibromyalgia. Mean anxiety and depression subscale scores were calculated, and proportions of patients by symptom severity were determined. The difference between the proportion of patients reporting anxiety and depression at baseline was tested using McNemar s test. Baseline anxiety and depression were evaluated as covariates by including them as interaction terms with treatment in an ancova model. A path analysis evaluated the association between improvements in anxiety and depression and pain relief. Results. In total, 529 patients were enrolled. Significantly more patients reported anxiety symptoms (71%) than depressive symptoms (56%) (P < ). Improvement in pain symptoms with pregabalin compared with placebo did not depend linearly on baseline anxiety or depression scores. By path analysis, 75% of the pain reduction was not explained by improvements in anxiety and depressive symptoms. Conclusions. Anxiety symptoms were more common than depressive symptoms in this cohort. Our results suggest patients with fibromyalgia should be routinely assessed for the presence of both anxiety and depression. The pain treatment effect of pregabalin did not depend on baseline anxiety or depressive symptoms, suggesting pregabalin improves pain in patients with or without these symptoms. Much of the pain reduction appears to be independent of improvements in anxiety or mood symptoms. Key Words. Fibromyalgia; Pain; Anxiety; Depression; Pregabalin Introduction F ibromyalgia is a chronic pain disorder of unknown etiology that is defined by the American College of Rheumatology (ACR) 1990 criteria as widespread pain of at least 3 months duration in combination with pain on palpation Reprint requests to: Lesley M. Arnold, MD, 222 Piedmont Avenue, Suite 8200, Cincinnati, OH 45219, USA. Tel: ; Fax: ; Lesley. Arnold@uc.edu. of at least 11 of 18 specific tender point sites on the body [1]. Fibromyalgia occurs in approximately 2% of the general population in the USA and is more common in women than in men [2]. In studies of both community and clinic groups, fibromyalgia is strongly associated with anxiety and depressive symptoms, with about one-third of patients reporting major current problems with anxiety or depression [2,3]. In clinical studies of patients with ACR-defined fibromyalgia, any current anxiety disorder has been American Academy of Pain Medicine /07/$15.00/ doi: /j x

2 634 Arnold et al. found in 27% to 60% of patients with fibromyalgia [4,5], and any lifetime anxiety disorder (both current and past) has been reported in 35% to 62% of patients [4,5]. The rates of current major depressive disorder have ranged from 14% to 23% [4,6,7], while lifetime diagnoses of major depressive disorder have varied between 58% and 86% [4,6 8]. The potential impact of comorbid anxiety and depressive symptoms on the response to treatment of fibromyalgia is an emerging area of research [9 11]. In this study, we assessed anxiety and depressive symptoms, using the patient-reported Hospital Anxiety and Depression Scale (HADS) [12] in a large cohort of patients participating in a randomized, controlled, monotherapy trial of pregabalin in fibromyalgia [13]. The goals of these analyses were to determine the prevalence and severity of anxiety and depressive symptoms in one of the largest groups of fibromyalgia clinical trial participants that has ever been studied and to evaluate the impact of baseline anxiety and depressive symptoms and change in these symptoms on response (i.e., pain reduction) to treatment with pregabalin. Methods Patient Selection and Assessment Full details of patient selection and assessment are presented in Crofford et al. (2005) [13]. Briefly, we recruited women or men aged 18 years who met the ACR criteria for fibromyalgia [1]. They were required to have a score of 40 mm on the 100-mm visual analog scale of the Short-Form McGill Pain Questionnaire [14] at screening and randomization (baseline) and a mean score 4 on a 0 10 pain rating scale based on at least four daily pain diary entries, during the week before randomization. Patients were excluded if they had inflammatory rheumatic disease or other severe painful disorders. Patients were also excluded if they had clinically significant or unstable medical or psychiatric conditions that, in the opinion of the investigator, would compromise participation in the study. Patients were required to discontinue all medications for pain and sleep disorders, as well as other psychotropic medications, at least 7 days before randomization (30 days for fluoxetine). Patients who were receiving disability, applying for disability, or engaged in litigation related to fibromyalgia were excluded. All patients gave written, informed consent. The randomized, double-blind, parallel-group 8-week clinical trial of pregabalin in the treatment of fibromyalgia was conducted between September 1999 and April 2000 at 40 study centers in the United States. Full details of the study design are presented in Crofford et al. (2005) [13]. The primary goal of the trial was to compare the effects of pregabalin treatment with those of placebo on reduction of pain severity. As part of the baseline assessment, before patients began study medication, and at endpoint, the patients completed the HADS [12], a widely used, self-reported, 14-item instrument that consists of two subscales of seven items: an anxiety subscale (HADS-A) and a depression subscale (HADS-D). The score for each subscale ranges from 0 (no anxiety or depression) to 21. Zigmond and Snaith (1983) [12] suggested subscale cut-offs of greater than or equal to 8 to indicate the likely presence of clinically significant levels of depression or anxiety at mild intensity and cut-offs of greater than or equal to 11 to indicate moderate to severe intensity. The HADS is a reliable and valid instrument for the assessment of anxiety and depression in medical patients and performs well in separately assessing anxiety and depressive symptom severity [15,16]. Pain was evaluated in a daily diary using a 0 10 numerical rating scale where 0 = no pain and 10 = worst possible pain. Baseline pain was defined as the mean of the last seven diary entries prior to start of study drug, and endpoint pain was defined as the mean of the last seven entries while on study drug. Statistical Analysis The mean anxiety subscale (HADS-A) and depression subscale (HADS-D) scores were calculated, and the proportions of patients with scores 7 (indicating no clinically significant anxiety or depressive symptoms), scores 8 and <11 (indicating mild anxiety or depressive symptoms), and scores 11 (indicating moderate to severe symptoms) were determined. The difference between the proportion of patients reporting anxiety at baseline and the proportion reporting depression at baseline was tested using McNemar s test. Baseline anxiety and depression symptoms were evaluated as covariates to predict endpoint pain by adding them, as continuous scores, as interaction terms with treatment, to an analysis of covariance (ancova) model that also included factors for treatment group, study center, and baseline pain score as the covariate.

3 Anxiety and Depression in Fibromyalgia Patients 635 Table 1 Baseline characteristics of the fibromyalgia patients* Characteristic All Patients, N = 529 Women, N (%) 484 (91) Race, N (%) White 493 (93) African American 12 (2) Hispanic 18 (3) Other 6 (1) Age, years 48.6 ± 10.6 Duration of fibromyalgia, months ± Pain score 7.0 ± 1.3 * Except where indicated otherwise, values are the mean ± SD. Based on daily diary entries recording pain on an 11-point scale ranging from 0 (no pain) to 10 (worst pain). Path analysis based on linear regression models was used to describe the association between improvements in anxiety and depression and pain relief. Overall pain relief was separated into components, the part of the pain relief that can be explained by improvements in anxiety and depression and the part that cannot be explained by improvements in anxiety and depression. This is accomplished by using a regression model in which pain relief is predicted by changes in anxiety and depression. The explained and unexplained components are sometimes referred to as indirect and direct treatment effects, respectively. Confidence intervals were calculated for each of these components based on bootstrapped samples. Results Details about the results of the primary study are reviewed in Crofford et al. (2005) [13]. Briefly, of 825 patients who were screened, 530 patients with fibromyalgia were randomized and 529 took at least one dose of study medication and were included in the analysis. A total of 410 patients (77.5%) completed the 8-week study. All of the 529 randomized patients completed the HADS and pain score at baseline. Table 1 shows the demographic and clinical characteristics of the patients; further details are presented elsewhere [13]. Table 2 summarizes the change in pain severity scores and HADS scores from baseline to endpoint, using endpoint analyses based on last observation carried further as described in detail previously [13]. As reported in Crofford et al. (2005) [13], pregabalin at a dose of 450 mg/day significantly reduced pain severity compared with placebo. Baseline mean HADS scores (SD) fell in the mild range: 10.1 (4.3) for anxiety symptoms; 8.6 (4.0) for depression. The proportions of patients Table 2 Baseline and endpoint ANCOVA values for the pain outcome measure and HADS* Parameter, Scale Overall Mean (SD) at Baseline Placebo Pregabalin 450 mg/day N LSM N LSM Pain diary, (1.3) HADS, 0 21 Anxiety 10.1 (4.3) Depression 8.6 (4.0) * The mean pain score and HADS in the pregabalin groups were compared with those in the placebo group using analysis of covariance (ancova) with treatment and center as the main effect and the baseline value as the covariate. Adjusted LSM were obtained from the model and 95% confidence intervals on the difference in between pregabalin and placebo were constructed [13]. P vs placebo. HADS = Hospital Anxiety and Depression Scale; LSM = least squares means. by HADS-A severity scores were as follows: 7, 29%; 8 and <11, 26%; 11, 45%. The proportions of patients by HADS-D severity scores were as follows: 7, 44%; 8 and <11, 26%; 11, 30%. The proportion of patients with any anxiety symptoms (71%) was significantly higher (P < ) than the proportion of patients with any depressive symptoms (56%), and 49% of patients reported both anxiety and depressive symptoms. The Pearson correlation between anxiety and depressive symptoms, as continuous variables, was In addition, neither the anxiety-by-treatment nor the depression-by-treatment interactions were significant (P = for each), suggesting that the improvement in fibromyalgia pain symptoms with pregabalin compared with placebo does not depend linearly on baseline HADS anxiety or depression scores. Overall, pain severity scores in the pregabalin 450-mg/day treatment group were 0.97 points lower than placebo. As indicated in Figure 1, the treatment effect in pain relief can be separated into three components. Using a path analysis approach, approximately 25% of the pain relief can be explained by the combined improvements in anxiety and depression, split evenly between the two. Pregabalin 450 mg/day a Anxiety = 0.14 * = (12.4%) a Depression = 0.16 * = (12.4%) b Unexplained = (75.3%) a Parameter estimate from regression model * treatment effect b Parameter estimate from regression model Total treatment effect on pain relief = Figure 1 Path analysis indicating the direct (unexplained) effect of pregabalin on pain reduction and the indirect effects attributed to change in anxiety and depressive symptoms.

4 636 Arnold et al. The remaining 75% of the pain relief cannot be explained by improvements in anxiety or depression. The 90% confidence intervals for these effects are 57 85% for the unexplained effect and 15 43% for the combined explained effects. Discussion A total of 529 fibromyalgia patients who enrolled in a randomized, monotherapy, controlled trial of pregabalin completed the HADS at baseline to assess anxiety and depressive symptoms. More than half the patients had at least mild levels of anxiety or depressive symptoms, according to suggested cut-offs of the HADS-A (anxiety) and HADS-D (depression) subscales [12]. The percentage of patients with at least mild anxiety (71%) was significantly higher than the percentage with at least mild depressive symptoms (56%). Furthermore, more patients (45%) reported moderate or severe levels of anxiety than moderate or severe depression (31%). Forty-five percent of the fibromyalgia patients in this clinical trial reported moderate to severe symptoms of anxiety, which is consistent with previous findings of any current anxiety disorder in up to 60% of fibromyalgia patients in clinical settings [4,5]. Relative to depressive symptoms, the assessment of anxiety symptoms in treatment trials of fibromyalgia has received even less attention. Anxiety disorders have been relatively neglected in chronic pain studies in general, but there is a growing awareness of the strong association of anxiety disorders with chronic pain conditions [17]. The finding that 30% of patients reported moderate to severe current symptoms of depression is consistent with previous findings of current major depressive disorder in up to 23% of fibromyalgia patients in clinical settings [4,6,7]. It is also consistent with a community study in which current depression was reported to be a major problem in about one-third of individuals with fibromyalgia [3]. Despite evidence of elevated rates of depressive symptoms in patients with fibromyalgia and the possible prognostic significance of depression, few previous clinical trials have administered standardized psychometric instruments to measure depressive symptoms [9 11]. The results of this study suggest that patients with fibromyalgia should be routinely assessed for the presence of depression. Furthermore, the observation in the present study that more patients reported anxiety symptoms than depression suggests that further attention should be given to the assessment of anxiety. The frequent presence of anxiety and depressive symptoms in the patients with fibromyalgia provides support to the hypothesis that there are shared risk factors for fibromyalgia and anxiety and mood disorders [18,19]. Evidence from two recent family studies of fibromyalgia suggests that fibromyalgia and mood disorders share common, and possibly genetic, determinants [18,20,21]. Further evidence linking fibromyalgia to anxiety and mood disorders is based on the responsiveness of these conditions to similar pharmacologic treatments [19]. Pregabalin modulates hyperexcited neurons by potent binding at the α 2 -δ subunit protein that is associated with decreased calcium influx at nerve terminals and reduced release of several excitatory neurotransmitters (including glutamate, norepinephrine, and substance P) [22 25]. Preclinical animal studies indicated that this mechanism of action may be responsible for the anticonvulsant, analgesic, and anxiolytic activity of pregabalin [26]. As previously reported [13], pregabalin at 450 mg/day significantly reduced the average severity of pain associated with fibromyalgia compared with placebo. In other studies, pregabalin has also been shown to be efficacious in the treatment of generalized anxiety disorder [27 31]. Therefore, one possibility is that improvements in pain scores seen in the fibromyalgia trial could be related to the positive anxiolytic effects of pregabalin. However, in the present study, we found that the pain treatment effect of pregabalin did not depend linearly on baseline HADS anxiety or depression scores, which suggests that pregabalin is likely to be efficacious in reducing pain in patients with or without comorbid anxiety or depressive symptoms. Furthermore, the path analysis showed that pain-relieving effects of pregabalin were largely independent of modulation of anxiety or depressive symptoms. Therefore, fibromyalgia may share underlying pathophysiologic links with anxiety and depression, but the independent effects of pregabalin on pain associated with fibromyalgia suggest that the pain reducing effects of pregabalin are not dependent on modulation of anxiety or depressive symptoms. Several limitations of this study should be considered. First, the patients were recruited for a clinical trial, and the findings may not generalize to other settings. Furthermore, patients with clinically significant or unstable psychiatric conditions were excluded. In addition, patients were required

5 Anxiety and Depression in Fibromyalgia Patients 637 to discontinue all psychotropic medications, such as anxiolytics or antidepressants, possibly eliminating patients who were unable to withdraw from medication for anxiety or mood disorders. Therefore, these data may underestimate the rates of anxiety and depressive symptoms in an unselected population of patients with fibromyalgia. Furthermore, patients with clinically significant or unstable psychiatric conditions were excluded if the investigator determined that the condition would compromise participation in the study. Psychiatric diagnostic interviews were not conducted, so the proportions of patients with undiagnosed anxiety or depressive disorders are unknown. However, it is likely that patients with mood or anxiety disorders were included if the investigator determined that the patients were stable enough for inclusion into the study. Although patients were not evaluated with structured psychiatric interviews, the self-report measure allowed for an assessment of the severity of symptoms along a continuum. As the results indicate, a substantial number of patients reported moderate to severe symptoms of anxiety or depression, which is consistent with previous studies of patients with fibromyalgia. Future studies should include a comprehensive assessment of psychiatric comorbidity using structured clinical interviews along with self-report assessments to provide more information about the presence, severity, and impact of psychiatric symptoms and comorbidity on the treatment of fibromyalgia. Second, the path analysis is based on a statistical method that models the correlation between simultaneously measured outcomes and, as a result, cannot establish causality. The proportion of the treatment effect that can be explained by improvements in comorbid symptoms, sometimes called the indirect effect, is often misinterpreted as quantifying how much improvement in the primary parameter is caused by improvements in comorbid symptoms. The proportion of pain relief associated with improvements in anxiety and depression, for example, does not suggest that 25% of patients get pain relief following improvements in anxiety or depression but only that 25% of patients report relief that is accompanied by improvements in anxiety or depression. Even if 95% of the pain relief could be explained by improvements in anxiety and depression, this does not demonstrate that pain relief follows from relief of anxiety or depression. It would only suggest that the correlation between pain relief and relief of anxiety and depression is high. Finally, most of the patients with fibromyalgia in this study were women. Therefore, it is possible the results would not generalize to men with fibromyalgia. Conclusion Because of the frequent presence of anxiety and depressive symptoms in patients with fibromyalgia, clinicians should inquire about these symptoms when evaluating and treating patients with fibromyalgia. In addition, clinical trials of fibromyalgia treatment should include an assessment of psychiatric comorbidity and an evaluation of the effect of psychiatric symptoms on response to treatment. The overall outcome of treatment in fibromyalgia patients will be determined by both the improvement in pain and also the response of associated symptoms. The effect of pregabalin on pain reduction appears to be independent of its effect on anxiety or mood symptoms. In addition, pregabalin reduced pain in patients with or without anxiety or depressive symptoms, suggesting that pregabalin would be efficacious in patients with or without these comorbid psychiatric symptoms. References 1Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Arthritis Rheum 1990;33: Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 1995;38: White KP, Nielson WR, Harth M, Ostbye T, Speechley M. Chronic widespread musculoskeletal pain with or without fibromyalgia: Psychological distress in a representative community adult sample. J Rheumatol 2002;29: Epstein SA, Kay G, Clauw D, et al. Psychiatric disorders in patients with fibromyalgia. Psychosomatics 1999;40: Malt EA, Berle JE, Olafsson S, Lund A, Ursin H. Fibromyalgia is associated with panic disorder and functional dyspepsia with mood disorders. A study of women with random sample population controls. J Psychosom Res 2000;49: Hudson JI, Goldenberg DL, Pope HG Jr, Keck PE Jr, Schlesinger L. Comorbidity of fibromyalgia with medical and psychiatric disorders. Am J Med 1992;92: Walker EA, Keegan D, Gardner G, et al. Psychosocial factors in fibromyalgia compared with rheumatoid arthritis: I. Psychiatric diagnoses and functional disability. Psychosom Med 1997;59:

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